Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Area of Science:

• Genetics
• Psychiatry
• Genomic Medicine

Background:

• Bipolar disorder (BD) is a significant mental illness with known common genetic influences.
• The contribution of rare genetic variations to BD etiology remains largely uncharacterized.
• Understanding rare variant burden is crucial for a comprehensive genetic model of BD.

Purpose of the Study:

• To investigate the role of rare, protein-altering, pathogenic or likely pathogenic (P-LP) variants in bipolar disorder.
• To assess the burden of these variants exome-wide and in biologically relevant gene sets.
• To examine potential shared rare variant associations between bipolar disorder and schizophrenia.

Main Methods:

• Exome sequencing data from 3,987 individuals with BD and 5,322 controls of European ancestry.
• Analysis of rare P-LP variants across the exome and in specific gene groups (BD GWAS, SCZ GWAS, neuronal synaptic genes, LoF intolerant genes).
• Replication analysis in an additional 9,929 BD cases and 14,018 controls.

Main Results:

• An initial enrichment of rare P-LP variants in BD GWAS genes did not replicate in a larger cohort.
• No significant enrichment of rare P-LP variants was found exome-wide or in other targeted gene sets in BD.
• No significant enrichment of P-LP variants was observed in schizophrenia-associated genes in the BD cohort.

Conclusions:

• This large-scale exome sequencing study demonstrates no replicable enrichment of rare P-LP coding variants in bipolar disorder.
• Rare coding variation does not appear to be a primary genetic factor contributing to BD risk.
• Despite shared common variant heritability, rare coding variants in schizophrenia-associated genes do not explain BD risk.